Optically active thiophenes via an organocatalytic one-pot methodology

Article abstract of DOI:10.1021/ol203237r

A general methodology for the synthesis of trisubstituted, optically active thiophenes by an organocatalytic one-pot reaction cascade is presented. The target products are synthesized in good yields (up to 92%) and with excellent enantioselectivities (up to 98% ee). Importantly, based on practical and easily available starting materials, the presented methodology can be conducted under mild reaction conditions. To further elucidate the generality, the synthesis of optically active thienoindoles, as well as selenophenes, is also demonstrated.

Full text of DOI:10.1021/ol203237r

ORGANIC
LETTERS
2012
Vol. 14, No. 3
724–727
Optically Active Thiophenes via an
Organocatalytic One-Pot Methodology
Lars Krogager Ransborg, Łukasz Albrecht, Christian F. Weise, Jesper R. Bak, and
Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, 8000 Aarhus C,
Denmark
kaj@chem.au.dk
Received December 5, 2011
ABSTRACT
A general methodology for the synthesis of trisubstituted, optically active thiophenes by an organocatalytic one-pot reaction cascade is
presented. The target products are synthesized in good yields (up to 92%) and with excellent enantioselectivities (up to 98% ee). Importantly,
based on practical and easily available starting materials, the presented methodology can be conducted under mild reaction conditions. To further
elucidate the generality, the synthesis of optically active thienoindoles, as well as selenophenes, is also demonstrated.
Heteroaromatic compounds constitute an important
class of molecules which are widespread in nature as well
as among synthetically obtained products.1 Their structur-
al rigidity and distinct electronic properties allow for consi-
derable fine-tuning of molecular properties. Among the
heteroaromatic frameworks, thiophenes occupy a promi-
nent position.2 While polysubstituted thiophenes are well
studied, their synthesis often relies on the functionalization
of simpler thiophenes, whereas methods for their construc-
tion from acyclic precursors are scarce. An example of
major importance is the Gewald synthesis, which affords
2-aminothiophenes.3 This well-studied multicomponent
reaction utilizes elemental sulfur for the introduction of
the thiophene sulfur atom and benefits from mild reaction
conditions, high efficiency, and easily available starting
materials (Scheme 1, left). An alternative methodology
for the preparation of thiophenes has been reported,4 in
which the sulfur atom is introduced by thioamides, a class
of practical and easily available molecules that have found
wide applications for the construction of heterocyclic
scaffolds (Scheme 1, right).5
Scheme 1. 2-Aminothiophene Annulation Strategies
(1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.;
Blackwell: Oxford, U.K., 2010. (b) Comprehensive Heterocyclic Chem-
istry: The Structure, Reactions, Synthesis, and Uses of Heterocyclic
Compounds, Vols. 1À8; Katrizky, A. R., Rees, C. W., Eds.; Pergamon
Press: Oxford, U.K., 1984. (c) Hetarenes and Related Ring Systems,
Science of Synthesis, Category 2, Vol. 10; Thomas, E. J., Ed.; Georg
Thieme Verlag: Stuttgart, 2000. (d) Gilchrist, T. L. J. Chem. Soc., Perkin
Trans. 1 2001, 2491.
(2) (a) The Chemistry of Heterocyclic Compounds: Thiophene and Its
Derivatives, Vol. 44, Parts 1À4; Weissberger, A., Taylor, E. C., Eds.;
€
Wiley: New York, USA, 1991. (b) Gronowitz, S; Hornfeldt, A. B. Thiophenes;
Elsevier: Oxford, U.K., 2004.
(3) For recent reviews, see: (a) Puterova, Z.; Krutosıkova, A.;
(4) For examples, see: (a) Moghaddam, F. M.; Boinee, H. Z.
Tetrahedron 2004, 60, 6085. (b) Reddy, K. V.; Rajappa, S. Heterocycles
1994, 1, 347.
ꢀ
ꢁ
ꢀ
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€
Vegh, D. ARKIVOC 2010, No. i, 209. (b) Huang, Y.; Domling, A.
Mol. Diversity 2011, 15, 3.
ꢀ
(5) For a review, see: Jagodzinski, T. S. Chem. Rev. 2003, 103, 197.
r
10.1021/ol203237r
Published on Web 01/18/2012
2012 American Chemical Society

As a result of the limited availability ofannulativestrate-
gies, investigations on formation of optically active
thiophenes rely predominantly on functionalization
of prochiral heteroaromatic starting materials.6 Con-
sequently, access to polysubstituted products is limited by
the availability of the parent thiophenes. A direct strategy
for the formation of optically active polysubstituted thio-
phenes from acyclic precursors is therefore of intriguing
interest.
substrates. A selection of bases and solvents were screened
(see Supporting Information for details), with Cs2CO3 in
toluene at 60 °C proving superior, providing the desired
thiophene 8a in 72% yield, with excellent enantioselectiv-
ity. Importantly, an alternative elimination pathway lead-
ing to the achiral thiophene 10 was identified, resulting
in yield deterioration. Therefore, investigations on the
aromatization step were undertaken. When the annulation
reaction was performed at room temperature, clean con-
version to dihydrothiophene 6a was observed. Delight-
fully, subsequent addition of acid promoted clean product
formation, and while other acids gave similar results, silica
was found to be the most convenient, affording 8a in 91%
yield and 96% ee (Table 1, entry 1).
Scheme 2. Organocatalytic One-Pot Methodology for the
Synthesis of Optically Active Thiophenes
Table 1. Aldehyde Scope for the Formation of Aminoalk-
ylthiophenes 8a
yield
[%]
eeb
[%]
entry
R
product
1
2
3
4c
5
6
7
8
Hex
Pr
8a
8b
8c
8d
8e
8f
91
83
92
80
81
60
82
83
96
95
93
89
95
94
96
92
Pursuing this challenge, it was envisioned that readily
available R,β-unsaturated aldehydes 1 could serve as a
starting point for an organocatalytic one-pot approach
(Scheme 2).7 After transformation of 1 to the aziridine- or
epoxy-aldehyde 3 or 4, subsequent reaction with a thio-
amide 5 under basic conditions followed by aromatization
would form the desired thiophene 8 or 9. One major chal-
lenge to this strategy would be to overcome the undesired
elimination pathway leading from the intermediate 6 or 7
to the achiral disubstituted thiophene 10. Herein, the
efficient enantioselective synthesis of polysubstituted thio-
phenes, as well as related heteroaromatic structures, is
reported.
iPr
Me
(E)-Hex-3-enyl
(Z)-Hex-3-enyl
CH2OTBDMS
CH2CH2Ph
8g
8h
a Reactions performed on a 0.1 mmol scale in 0.5 mL toluene (see
Supporting Information for details). Nomenclature legend: Type A: the
position of the enantio-differentiating manual operation (at the start); 3:
the number of manual operations; 1C2X: the number of CÀC bonds
(mC) and CÀX bonds (nX) formed; AOC: asymmetric organocatalysis;
ANN: annulation; ELN: elimination reaction. b Determined by chiral
stationary phase HPLC. c Crotonaldehyde was utilized as a 97:3 E/Z
mixture.
Optimization studies were conducted using nonenal 1a
and methyl 3-(dimethylamino)-3-thioxopropanoate 5a as
With the optimized reaction conditions established, the
scope of this TypeA-3-1C2X cascade7f was investi-
gated (Table 1). A selection of R,β-unsaturated aldehydes
carrying primary and secondary alkyl substituents were
successfully employed, all giving rise to the target thio-
phenes in excellent yields and enantioselectivities (Table 1,
entries 1À4). Moreover, side chain functional groups were
successfully introduced, providing equally good results
(Table 1, entries 5À8). Ethyl 4-oxobut-2-enoate was also
tested but disappointingly resulted in a complex reaction
mixture.
(6) For selected recent examples, see: (a) Bonini, C.; Chiummiento,
L.; De Bonis, M.; Funicello, M. Tetrahedron: Asymmetry 2006, 17, 2919.
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107, 5413 (special issue on organocatalysis). (b) Dondoni, A.; Massi, A.
Angew. Chem., Int. Ed. 2008, 47, 4638. (c) MacMillan, D. W. C. Nature
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In an attempt to broaden the scope of the reaction
for inclusion of hydroxyalkyl substituted thiophenes, the
Org. Lett., Vol. 14, No. 3, 2012
725

ability of epoxy-aldehyde intermediates to take part in the
developed reaction sequence was investigated (Table 2).
that the application of nucleophiles 5 carrying inductively
electron-withdrawing groups, e.g. trifluoromethyl and
pentafluorophenyl, did not lead to product formation.
Studies were therefore limited to electron-withdrawing
groups allowing for mesomerical stabilization (Scheme 3).
Introduction of nitrile (8k, 9k) or ketone (8n, 9n) sub-
stituents was compatible with both epoxide and aziridine
intermediates. Contrarily, a nucleophile carrying a 2,
4-dinitrophenyl substituent resulted in good yield and
excellent enantioselectivity for the aminoalkyl thiophene
8l, whereas no reaction occurred when applied to the
epoxide intermediate. The incorporation of a Weinreb
amide was also demonstrated; however, while satisfying
results were obtained for 8m, the hydroxyalkyl substituted
thiophene 9m was highly prone to racemization.
Table 2. Aldehyde Scope for the Formation of Hydroxyalk-
ylthiophenes 9a
yield
[%]
eeb
[%]
entry
R
product
Scheme 3. Nucleophile Scope for the Formation of Thiophenes
8 and 9a
1
2
3
4c
5
6
7
8
Hex
Pr
9a
9b
9c
9d
9e
9f
75
74
61
33
73
40
71
72
94
94
98
86
96
92
96
94
iPr
Ph
(E)-Hex-3-enyl
(Z)-Hex-3-enyl
CH2OTBDMS
CH2CH2Ph
9g
9h
a Reactions performed on a 0.1 mmol scale in toluene (see Supporting
Information for details). b Determined by chiral stationary phase HPLC.
c 10 mol % catalyst applied.
Satisfyingly, the previously developed methodology for
epoxidation of R,β-unsaturated aldehydes in toluene8
proved compatible with the optimized thioamide approach,
resulting in a TypeA-2-1C2X reation cascade. As for the
aziridine scope, linear and γ-branched R,β-unsaturated
aldehydes gave rise to the desired thiophenes with excellent
enantioselectivities and good yields (Table 2, entries 1À3).
Cinnamaldehyde was also tested, resulting in the desired
aryl substituted product 9d, albeit in moderate yield and
slightly reduced enantiomeric excess (Table 2, entry 4).
Furthermore, incorporation of a range of functionalities in
the side chain was demonstrated, with little influence on
the efficiency of the cascade (Table 2, entries 5À8). As
observed for the aminoalkyl thiophene scope, the applica-
tion of ethyl 4-oxobut-2-enoate in the reaction gave unsat-
isfactory results, which was alsofound for crotonaldehyde.
In the interest of achieving higher substituent diversity,
investigations on the application of other nucleophiles
were conducted (Scheme 3). The dimethyl thioamide motif
was successfully replaced with a cyclic morpholine deriva-
tive, leading to the formation of 8i and 9i. A secondary thio-
amide group, carrying a para-methoxyphenyl N-protecting
group, was also tolerated (8j, 9j), principally allowing
access to a Gewald-type primary amine substitution pattern.
Application of a phenyl ring as an electron-withdrawing
group was unsuccessful, and furthermore, it was demonstrated
a See Supporting Information for details.
To further elucidate the versatility of the developed
cascade, the synthesis of compounds closely related to
thiophenes was studied. Thieno[2,3-b]indoles are struc-
tures consisting of a fused aromatic three-ring system
containing a nitrogen and a sulfur heteroatom. Interesting
biological properties of these systems have been de-
scribed,9 but few methods for their preparation exist.10 It
was envisioned that the application of 2-thioindole 11 as a
nucleophile in the developed reaction sequence would
allow for the synthesis of unprecedented optically active
thieno[2,3-b]indoles 12 (Scheme 4, right). Preliminary results
indicated that the direct application of the optimized
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726
Org. Lett., Vol. 14, No. 3, 2012

TypeA-3-1C2X cascade was unsuccessful, leading to fast
decomposition of the reactants. However, under base-
free conditions, 1-methylindoline-2-thione 11 could be
reacted with the intermediate aziridine-aldehyde resulting
in formation of the desired aminoalkyl thieno[2,3-b]-
indole 12 with excellent enantioselectivity and acceptable
yield, thus proving the concept of this pathway. In con-
trast, the application of epoxy-aldehydes in the reaction
sequence led to the formation of the desired product in low
yields when dichloromethane was usedas solvent. Further-
more, fast racemization of the product was observed.
the directly analogous and easily obtainable selenoamide
13 as a prime candidate. The reaction cascades proceeded
with excellent stereoselectivities, giving rise to the target
selenophenes 14a and 14b in 87% and 73% yield, respec-
tively (Scheme 4, left). The close resemblance to the results
obtained for thiophenes indicates that the developed strat-
egy can be directly applied as a general method for the
preparation of selenophenes.
The assignment of the absolute configuration of the
obtained products 8, 9, 12, and 14 is based on studies on
the organocatalytic epoxidation and aziridination of R,
β-unsaturated aldehydes and their application in target
oriented one-pot reaction cascades.8b,13 To support these
assignments, the crystal structure of 8b was obtained
by X-ray analysis, unambiguously confirming the R-
configuration.14
Scheme 4. Synthesis of Thienoindoles 12 and Selenophenes 14a
Inconclusion, anefficient andhighlystereoselectiveone-
pot methodology for the synthesis of optically active
thiophenes, thieno[2,3-b]indoles, and selenophenes has
been described. The developed cascades rely on a highly
enantioselective amino-catalyzed epoxidation or aziridina-
tion reaction, combined with a ring annulation, to afford
the target compounds. These reactions can be carried out
under mild reaction conditions and are based on the
application of convenient, easily obtainable reagents.
The scope of the thiophene formation has been thoroughly
investigated, demonstrating wide functional group toler-
ance resulting in the high substitution diversity of the final
aromatic framework.
a See Supporting Information for details.
Selenophenes are closely related to thiophenes and
furans, originating from incorporation of the third mem-
ber of the chalcogen group. Although organoselenium
compounds share many properties with their sulfur coun-
terparts, selenophenes have been investigated for their
distinct properties.11 The formation of an optically active
selenophene through coupling to a chiral starting material
has also been reported.12 As is, an efficient methodology
for the formation of the selenophene motif in an asym-
metric fashion would be of major interest. Studies to
identify a suited nucleophile were therefore initiated, with
Acknowledgment. This work was made possible by
grants from FNU, OChemSchool, and the Carlsberg
Foundation. Thanks are expressed to Dr. Jacob Over-
gaard (Department of Chemistry, Aarhus University) for
performing X-ray analysis.
Supporting Information Available. Complete experi-
mental procedures and characterizations. This material is
available free of charge via the Internet at http://pubs.
acs.org.
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H. N.; Gurudutt, V. V.; Sint, T.; Schneider, B. P.; Jones, W. D.; Goldstein,
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J. Med. Chem. 1997, 40, 1731.
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V.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2009, 48, 6844. (b) Albrecht,
Ł.; Ransborg, L. K.; Gschwend, B.; Jørgensen, K. A. J. Am. Chem. Soc.
2010, 132, 17886. (c) Albrecht, Ł.; Ransborg, L. K.; Albrecht, A.; Lykke,
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(14) See Supporting Information for the crystal structure. CCDC
854647 (8b) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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